Allelic genotyping reveals a hierarchy of genomic alterations in mantle cell lymphoma associated to cell proliferation

Mantle cell lymphoma (MCL) is a distinct subentity of non-Hodgkin lymphoma, characterized by the chromosomal translocation t(11;14)(q13;q32) leading to an overexpression of cyclin D1 in virtually all cases. However, additional cytogenetic aberrations are apparent in the vast majority of MCL. Applying LOH analysis in 52 MCL patient samples, we confirmed frequent alterations in 9p21 (28.6%) and p53 (28.9%) but also detected allelic losses in 1p21, 9q21, 13q13-14, 13q31-32, 17p13.1, and 17p13.3 in 28-45% of cases and allelic gains in 3q27-28 and 19p13.3 in 14-22% of cases. In addition, losses in the 2p23 and 7q22-35 genomic regions not previously described to be altered in MCL were identified in up to 20% of cases. Applying multivariate analysis, a cluster of genomic aberrations including 1p21, 3q27, 7q22-36, 6p24, 9p21, 9q31, and 16p12 alterations was identified which was closely associated to cell proliferation as determined by Ki67 immunostaining. This proliferation-dependent network of oncogenic alterations complements the previously identified proliferation expression signature described by RNA expression profiling in MCL.